Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

PHA 332 > GOUT therapeutics > Flashcards

GOUT therapeutics Flashcards

1
Q

what is GOUT?

A

Gout is associated with a persistently raised
plasma uric acid (urate) concentration
Uric acid is relatively insoluble in water and too
much uric acid leads to uric acid crystal
formation
•Leads to painful inflammation within joints

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

what is the main source of plasma uric acid?

A

catabolism of the nucleic acid purine bases

guanine and adenine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what are the modifiable and non-modifable risk factors for GOUT?

A

modifiable- diet and obesity

non-modifiable- fam history, age, sex,medication, medical condition, racial background

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

who is GOUT more common in?

A

4x more likely in males

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

what race is GOUT more common in?

A

African Americans double risk factor compared to Caucasians, Possibly
Linked to hypertension and CKD
–Maori in NZ, Hmong population in China, Filipino population etc etc

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

what food increases your risk of GOUT?

A

Alcohol, red meat/seafood (purine rich foods), fructose/ sugar-sweatned bevrages

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

what foods decrease your risk of GOUT?

A

veg protein, dairy, coffee, vit C, cherries

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

how do genes influence GOUT?

A

•SLC22A12 gene encode for the urate transporter 1 URAT1 on the brush
border of proximal tubules in the kidney
•SLCA9 encodes for GLUT9 – a urate uniporter, also implicated in urate
reabsorption.
•SLC17A1 encodes for the NPT1 transporter
•ATP -Binding Cassette G2 ABCG2 is multidrug transporter in the renal tubules
also implicated in urate transport
•ALL integral in the process of urate reabsorption and excretion.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

how does purine get metabolised to uric acid?

A

Uric acid is the end product of purine nucleic
acid degradation
–Adenine and Guanine
nucleic acids>purines> hypoxanthine (XANTHINE OCIDASE)> Xanthine ( xanthine oxidase)> uric acid> renal excretion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

how does purine metabolism occur?

A 
Adenine and Guanine are metabolised 
through the same pathway
•Deamination occurs of Adenine
•Ribose-5-P removal 
•BOTH are converted to XANTHINE
–Treatment strategy later
•Finally stage is conversion to uric acid
•Uric acid is renally excreted
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

do humans metabise uric acid?

A

no
Humans only excrete relatively low levels of uric
acid
•Most nitrogen is excreted via the urea cycle
•Believed humans lost urate oxidase during
evolution

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

what variants are assoicated with hyperuricaemia and risk of GOUT?

A

SLC2A9 and SLC22A12

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what variants increase the serum urate levels and risk of gout?

A 
Dysfunctional variants (Q126X and Q141K) of ABCG2 strongly increase 
serum urate levels and the risk of gout
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what are other genetic abnormalities that lead to GOUT?

A

hypoxyxanthine-guanine-phosphoribosyltransferase (HGPRT) deficiency
•5’-phosphoribosyl-1’-pyrophosphate synthase (PRPP) deficiency

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

how does GOUT occur?

A

Gout arises when monosodium urate crystals (MSU) deposit in cartilage in
the joint space
Resulting from sustained hyperuricaemia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

do all patients with hyperuricameia develop GOUT?

A

–BUT not all patients with hyperuricaemia develop Gout – only 5% of
patients >9mg/dL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

what occurs in deposition of MSU crystals?

A

–Reduced solubility (supersaturation)
–Nucleation
–Crystal Growth
> inflam response

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

what is urate?

A

Urate is the ionised form of uric acid, Weak acid with a pH of 5.8

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

what is the pathological threshold of uric acid/?

A

Pathological threshold is >6.8mg/dL

–Above this level and crystallisation can occur

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

what factors affect the solubility of uric acid?

A 
Factors effecting solubility
–Synovial fluid pH
–Water concentration
–Electrolytes
–Proteoglycans/Collagen levels
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

how is uric acid excreted?

A

kidneys

22
Q

what are the 4 major causes of GOUT?

A
  1. Idiopathic decrease in uric acid excretion (~75% of cases of clinical gout)
  2. Impaired uric acid excretion secondary to thiazide diuretics, chronic renal
    failure, etc
  3. Increased uric acid production due to increased cell turnover (e.g.
    tumours), increased purine synthesis (specific enzyme defects)
  4. High dietary purine intake
23
Q

what are the causes of hyperuriceamiea?

A

overproduction of uric acid

reduced renal excretion of uric acid

24
Q

what causes overproduction of uric acid?

A

–excessive cell destruction e.g. treatment of lymphoproliferative or
myeloproliferative disorders
–Inherited defects that increase purine synthesis
–High purine intake such as red meat, fish, beer and spirits
–Metabolic syndrome obesity, insulin resistance, hypertension and
hyperlipidaemia

25
Q

what causes reduced renal excretion of uric acid?

A

–reduced tubular uric acid secretion, which may have a genetic
component
–renal failure
–drugs that compete for the tubular transporter for uric acid e.g.
diuretics, ciclosporin
–Low-dose aspirin also reduces uric acid excretion, but the effect is
probably clinically insignificant

26
Q

what happens when there is hyperuricaemia?

A 
precipitation of urate crystals in joint
1- activation of complement and kinin system
neutrophil chemotaxis
phagocytosis of crystals by neutrohils
lysis of neutrophils
release of lysosomonal enzymes
tissue injury and inflamation
or release or LTB4 prostaglandings, free radicals
  • phagocytosis by macrophages
    release of il1 , other cytokines
    neytrophil chemotaxis….
27
Q

what are the 4 common presentations of GOUT?

A
  1. Asymptomatic Gout
  2. Acute “gouty arthritis”
    –Swollen joint with inflammation
    –Pyrexia and erythematous
    –Caused by uric acid in the joint
    –Gout ‘flares’
  3. Asymptomatic inter-critical period
  4. Chronic tophaceous gout
    –After ~ 10 years
    –Occurrence of Tophi
    –May affect other surrounding tissues
28
Q

what is tophi?

A

region of chronic foreign body granulomatous

response surrounding collections of MSU crystals

29
Q

how do you diagnose gout?

A 
•Physician observation
•X-Ray, ultrasound
•Lab tests 
–Serum Uric Acid (SUA)
–CRP C-Reactive Protein
–ESR
•Gold Standard - MSU crystal detection 
in synovial fluid aspirates
•Rule out infection, tumours etc
•CVD and Renal tests
30
Q

what treatments are availible for GOUT?

A

•Prophylactic treatment
–Xanthine oxidase inhibitors
–Uricosuric drugs
–Uricase’s

•Symptomatic treatment
–Colchicine
–Corticosteroids
–Nonsteroidal anti-inflammatory agents

•Lifestyle modifications

31
Q

what is availible for acute GOUT management?

A

•NSAIDs – diclofenac, Indomethacin, Naproxen,
Piroxicam in conjunction with PPIs if necessary
•Etoicoxib – COX2 inhibitor licensed for Gout
management
•Corticosteroids - Presnisolone
RICE

32
Q

When would you use colchicine?

A

Second line – Colchicine, especially is NSAIDs

contraindicated

33
Q

how does colchicine work?

A

Colchicine modulates multiple pro- and anti-
inflammatory pathways associated with gouty
arthritis

34
Q

what does colchicine prevent?

A

Colchicine prevents microtubule assembly and
disrupts inflammasome and neutrophil activation
•Prevents microtubule-based inflammatory cell
chemotaxis, generation of leukotrienes and cytokines,
and phagocytosis impacting pain and inflammation

35
Q

does colchicine affect serum level conc?

A

no

36
Q

how do NSAIDS and colchicine work in GOUT?

A

PMNs release inflammatory leukotrienes that attract inflammatory cells
•Colchicine acts on microtubules in the inflammatory cells
•NSAIDs act on cyclooxygenase-2 (COX II) in all of the cells of the joint

37
Q

what is first line therapy?

A

urare lowering therapies0 inhibit uric acid synthesis

38
Q

what drugs inhibit uric acid synthesis?

A

Allopurinol inhibits Xanthine Oxidase

39
Q

what is allopurinol converted to?

A

Allopurinol is first converted to

Alloxanthine

40
Q

how does allopurinol work?

A 
Allopurinol reduces the 
concentration uric acid in all tissues
•Increases the more soluble 
precursors - xanthines and 
hypoxanthines. 
•The deposition of urate crystals in 
tissues (tophi) is reversed
41
Q

what is allopurinol’s half life?

A

Allopurinol is given orally and is well absorbed. Its half-life is 2–3 h: its
active metabolite alloxanthine has a half-life of 18–30 h. Renally excreted

42
Q

what are allopurinols s/e?

A

–Gastrointestinal disturbances,
–allergic reactions (mainly rashes)
–toxic epidermal necrolysis and Stevens–Johnson syndrome are rare

43
Q

when is allopurinol never initiated?

A

during an accute attack
Acute attacks of gout occur commonly during the early stages of therapy
so treatment with allopurinol is never initiated during an acute attack and
is usually combined with an NSAID initially.

44
Q

what is febuxostat?

A

is an alternative inhibitor which has a similar pharmacology
and MOA as Allopurinol - Xanthine Oxidase inhibitor

45
Q

when is febuxostat given?

A

Allopurinol is FIRST choice and give Febuxostat if allopurinol not tolerated

46
Q

what are uricosuric agents?

A

increase uric acid excretion by a direct action on the renal
tubule

47
Q

when are uricosuric agents given?

A

3rd line - Useful for prophylaxis for patients with severe recurrent gout who
have severe adverse reactions to allopurinol. Treatment with uricosuric
drugs is initiated together with an NSAID

48
Q

what transporters are proposed to be involved in uricacid reabsorption?

A

Several transporter proteins have been proposed to participate in uric acid
reabsorption e.g. URAT1 and GLUT9

49
Q

what do uricosuric agents do and give examples?

A

–Probenecid – popular until allopurinol developed
–Benzbromarone – potent but reports of hepatotoxicity
–Lesinurad – URAT1 inhibitor

50
Q

what do

Uricosuric Agents Target Transporters do?

A
  • Inhibition of Urate transporters prevent reabsorption
  • Increase renal excretion
  • Decrease in Uric acid / Urate levels in serum
51
Q

how do ra bioligics work in gout?

A

Competitively inhibits IL-1 binding to the
interleukin-1 type I receptor expressed in a
wide variety of tissues and organs
•Used in patients with rheumatoid arthritis
have elevated levels of IL-1

52
Q

how does rasburicase work?

A

Rasburicase, a preparation containing the
enzyme uric acid oxidase, is sometimes used for
aggressive treatment of gout.
•Oxidises uric acid in the blood to allantoin, which
is more soluble and thus more readily excreted.

PHA 332 (42 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions